The present invention relates to a catheter system having several components that is capable of delivering a drug, medication or any desirable substance into a selected site. These substances are usually applied to the desired site prior to making an incision or surgery on the same site. The present delivery systems usually involve a single catheter with an inflatable balloon made up of either a permeable or semipermeable material. Examples of the balloon catheters used for different applications are illustrated in U.S. Pat. No. 5,286,254 issued to Shapland et al., U.S. Pat. No. 4,299,227 issued to Harvey A. Lincoff, U.S. Pat. No. 4,327,734 issued to Robert I. White, Jr., U.S. Pat. No. 3,788,328 issued to Ralph D. Alley and David S. Sheridan and U.S. Pat. No. 5,100,383 issued to Meir Lichtenstein. The present invention is constructed differently from the other balloon catheters and the delivery system is composed of several parts. One specific application of this invention relates to the use of the catheter system in the management of glaucoma.
There are many techniques for delivering drugs and other substances or medication to body tissues and organs. These include among possible others, oral administration, injection directly into body tissue, topical administration, transcutaneous administration and intravenous administration. Direct injection into the tissue, oral administration, or intravenous administration typically delivers the desired substance into the blood stream and therefore tend to be systemic. Topical and transcutaneous administration tend to deliver the drug, medication or desired substance into a localized area. The drug, medication or desired substance is usually absorbed into or across the skin or tissue. Topical and transcutaneous application are suitable delivery systems if the desired site of application is the skin or tissues proximate to the skin and passive absorption of the drug or substance by the surrounding tissue is not critical. Although many medical situation are satisfactorily treated or managed by these various techniques, there is a need for a system that can deliver a drug or other desired substance into a localized area of an internal tissue or organ without appreciably affecting the surrounding tissues. This system would be particularly useful when an incision is subsequently made on the site after the localized application of the drug or substance.
There are several applications for which such system would be desirable. This system can be used to apply substances, medication or drugs such as antibiotics, anesthetics, and wound modulating agents like antimetabolites to a tissue or organ remote to the external parts of the body prior to an incision or surgery at the site of application. One particular application is the application of wound modulating agents to the episcleral space of the eye prior to the fistulizing step in the glaucoma filtering procedure. The filtering procedure is employed to manage glaucoma. Another particular application is for delivering wound modulating agents such as antimetabolites to scars subsequently formed after an unsuccessful glaucoma filtering procedure to enable formation of more permanent escape channels for the aqueous humor. Still another particular application is for delivering wound modulating agents to scars formed on and around implants placed in the fistula during the filtering procedure. The implants are placed to keep the fistula open. The implants consist of a wide variety of foreign materials placed in the fistula such as stripe of hydrogel with parallel capillary channels, tubes and valves made of biocompatible materials.
Glaucoma is a leading cause of irreversible blindness throughout the world. Glaucoma is characterized by widely diverse clinical and histopathologic manifestation. However, all glaucomas can be generalized as situations in which the intraocular pressure (hereinafter referred to as IOP) is too high for the normal functioning of the optic nerve head. Damage to the optic nerve head is associated with progressive loss and constriction of the visual field, and it is this which, if untreated, can lead to total, irreversible blindness. Blindness from glaucoma is preventable but requires early detection and proper treatment. Once the blindness of glaucoma has occurred, there is no known treatment that will restore the lost vision. Detection depends on the ability to recognize the early clinical manifestations of the various glaucomas, while appropriate treatment requires an understanding of the pathogenic mechanism involved, as well as a detailed knowledge of the drugs and surgical procedures that are used to control the IOP. In the eye, the bulk of aqueous humor which is produced by the ciliary processes flows through the pupil into the anterior chamber and leaves the eye via structures in the anterior chamber angle, primarily through the trabecular meshwork and Schlemm's canal with a small contribution from anterior uveal absorption. From Schlemm's canal, the aqueous humor passes through intrascleral channels to reunite with the blood stream in the episcleral veins. The normal pressure in these vessels is 8 to 11 mm Hg which contribute directly to the IOP. A rise in IOP occurs when the rate at which aqueous humor enters the eye is greater than the rate at which it leaves the eye.
One means for lowering the IOP in glaucoma patients is through the glaucoma filtering procedure. This procedure generally involves providing a limbal fistula through which the aqueous humor can drain into a subconjunctival space and subsequently filter into the conjunctiva. A limbal fistula means an opening at the limbus of the eye. There are two basic types of fistulas, a full thickness and a partial thickness fistula. A full thickness fistula is a direct opening through the full thickness of the limbal tissue. A partial thickness fistula is a fistula having a partial thickness scleral flap over it. There are several means for creating the fistula and there are also several variations for performing the filtering procedure. The present means usually involves formation of a scleral flap prior to the formation of the fistula. A scleral flap is usually formed by making a limbus-based conjunctival flap followed by dissection of a desired area of the sclera. Shields, M. B. (1982) Textbook of Glaucoma, 1st ed. pages 461-497 describes the different fistulizing techniques and filtering procedure. Most successful glaucoma filtering procedure are characterized by a fistula that remains open for the free flow of the aqueous humor. The most common cause of failure in glaucoma filtering surgery is scarring at the fistula and the immediate area around the filtering site. This usually occurs external to the scleral flap at the level of the conjunctiva-Tenon's capsule-episcleral interface. Scarring is characterized by an increased amount of collagen produced by the proliferation of fibroblasts which eventually blocks the fistula thereby preventing the free flow of the aqueous humor and the patient reverts back to the glaucoma condition. Preoperative and postoperative inflammation frequently also contributes to the scarring. A larger incision made prior to the formation of the fistula is expected to cause more inflammation thereby aggravating the scarring situation. Antimetabolites such as 5-fluorouracil, cytosine arabinoside, bleomycin, and doxorubicin had been shown to inhibit fibroblast proliferation. The antimetabolite treatment increases the success rate of the filtering procedure. Presently, the antimetabolite such as 5-fluorouracil (hereinafter referred to as fluorouracil) is usually injected subconjunctivally, several degrees from the operative site, several times after the glaucoma filtering procedure. Alternatively, fluorouracil is also given intraoperatively followed by the postoperative subconjunctival injections. Dose and frequency of injection differ according to the type of glaucoma. These treatment regimens are well documented in the literature. The necessity of multiple subconjunctival injections which inconvenience the patient coupled with the high incidence of conjunctival and corneal epithelial toxic effects manifested by conjunctival wound leaks and corneal epithelial defects have limited the widespread application of fluorouracil. Conjunctival wound leaks usually results from the passing of the aqueous humor from the filtering site directly through the conjunctival needle tracts because fluorouracil also effectively inhibits the conjunctival wound healing of the needle tracts which are formed during the suturing of the scleral flap after the filtering procedure. Wound modulating agents such as the antimetabolite fluorouracil inhibit fibroblast proliferation which affect collagen formation, resulting into inhibition of wound healing. Other wound modulating agents such as alkylating drugs or agents and natural alkaloids may also inhibit fibroblast proliferation. Examples of these wound modulating agents are mechlorethamine, cyclophosphamide, chlorambucil, melphalan, aziridine, alkyl sulfonate, carmustine, lomustine, semustine, triazene, streptozocin, methotrexate, cytarabine, mercaptopurine, thioguanine, vinblastine, vincristine, dactinomycin, daunorubicin, doxorubicin HCl, bleomycin, mitomycin, and plicamycin. Further caution is required on the use of wound modulating agents, in general, due to the reported complications of unexpectedn hypotony observed with its use. Hypotony means an intraocular pressure lower than 5 mm Hg.
Mitomycin-C, an example of a wound modulating agent, is an alkylating agent isolated from Streptomyces caespitosus, which can be used as an alternative to fluorouracil. Because Mitomycin-C (hereinafter referred to as mitomycin) can penetrate the anterior chamber and also cause endothelial damage, mitomycin unlike fluorcuracil, cannot be injected subconjunctivally after the filtering procedure. However, a single intraoperative application of mitomycin at the filtering site has been shown to be sufficient in inhibiting fibroblast proliferation because it is at least one hundred times more potent than fluorouracil. See Ando, Ido, Kawai, Yamamoto and Kitazawa, Inhibition of Corneal Epithelial Wound Healing, Ophthalmology 99:1809, Kitazawa, Kawase, Matsushita and Minobe, Trabeculectomy With Mitomycin, Arch. Ophthalmol. 109:1693, and Zacharia, Deppermann and Schuman, Ocular Hypotony After Trabeculectomy With Mitomycin C, Amer. J. Ophthalmol. 116:314. Intraoperative application of fluorouracil as used in the mitomycin treatment, even at higher concentrations and longer exposure times do not produce the same results as mitomycin. Mitomycin treatment, therefore, has greater success rates in the management of glaucoma compared to fluorouracil especially in patients with complicated glaucomas such as neovascular glaucoma, inflammatory glaucoma and patients whose previous filtration procedure had failed. This feature compared to multiple subconjunctival injection and the reduced incidence of corneal toxic effect brought about by the focal application of mitomycin are the major attractions of the mitomycin treatment. The primary effect of mitomycin appears to be a cytocidal effect on subconjunctival fibroblasts at the filtering site. One disadvantage of using mitomycin is the observed greater incidence of hypotony with mitomycin compared to fluorouracil. Hypotony in mitomycin treatment can generally be prevented by lower concentrations and less exposure times. The recommended time for mitomycin application is less than five minutes. Therefore, a process that results in a focal and timed exposure of mitomycin to the tissue is needed in order to limit its toxic effects. An application system capable of delivering a more concentrated mitomycin at a limited area for a controlled period of time is required as a delivery tool for the development of an application process that will result in a successful filtering procedure for the management of glaucoma.
Several techniques for the intraoperative application of mitomycin in filtering procedures are described in published literature. See Kitazawa, Kawase, Matsushita and Minobe, Trabeculectomy with Mitomycin, Arch. Ophthalmol. 109:1693-1698, Skuta, Beeson, Higginbotham, Lichter, Musch, Bergstrom, Klein, and Falck, Intraoperative Mitomycin versus Postoperative 5-Fluorouracil in High-risk Glaucoma Filtering Surgery, Ophthalmology 99:438-444, Palmer, Mitomycin as Adjunct Chemotherapy with Trabeculectomy, Ophthalmology 98:317-321, Kitazawa, Matsushita, Yamamoto, and Kawase, Low-dose and High-dose Mitomycin Trabeculectomy as an Initial Surgery in Primary Open-angle Glaucoma, Ophthalmology 100:1624-1628, Shields, Scroggs, Sloop and Simmons, Clinical and Histopathologic Observations Concerning Hypotony after Trabeculectomy with Adjunctive Mitomycin C, Amer. J. Ophthalmol. 116:673-683, Khaw, Doyle, Sherwood, Grierson, Schultz, and McGorray prolonged Localized Tissue Effects from 5-Minute Exposures to Fluorouracil and Mitomycin C, Arch. Ophthalmol. 111:263-267, and Wise, Mitomycin-Compatible Suture Technique for Fornix-Based Conjunctival Flaps in Glaucoma Filtration Surgery, Arch. Ophthalmol. 111:992-997. Although these procedures may differ slightly, the intraoperative application of mitomycin generally involves soaking a piece of sponge into a mitomycin solution and contacting the soaked sponge to the exposed scleral surface over the planned filtration site for a controlled period of time, generally less than 5 minutes or sequentially at several one minute exposures for a total of 5 minutes of tissue exposure. This is usually followed by a washing procedure to wash off the mitomycin from the filtration site. The present use of sponge for mitomycin application causes exposure of a wider surface of tissue than is required. As mentioned above, although mitomycin application prevents the scarring of the fistula, it is also more potent and more toxic to the exposed tissues than fluorouracil.
One object of the invention is to provide a catheter system capable of a timed introduction of a desired substance with minimal surgical disturbance resulting in less inflammation compared to the current procedure employed in the formation of the scleral flap. Another object of the invention is to provide a catheter system for introducing a desired but generally toxic substance into a localized area for a given length of time where prolonged exposure to the surrounding areas is not desirable. Examples of these substances are wound modulating agents such as antimetabolites alkylating drugs or agents, natural alkaloids and other fibroblast proliferation inhibiting agents which reduce collagen response to injury. Still another object of this invention is to demonstrate a process using the catheter system for introducing a desired but generally toxic substance like mitomycin prior to the fistulizing step of the filtering procedure used in the management of glaucoma. A further object of the invention is to show the use of the catheter system in correcting conditions where the glaucoma filtration procedure failed due to scar formation.